The present invention relates to an apparatus for noninvasive testing and monitoring of biological molecules such as glucose.
Diabetes mellitus is a medical condition in which the body does not adequately produce the quantity or quality of insulin needed to maintain normal levels of glucose in the circulating blood. The two most common types of diabetes are type I, also known as Insulin Dependent Diabetes Mellitus (IDDM), which accounts for 5-10% of all cases, and type II or Non-Insulin Dependent Diabetes Mellitus (NIDDM), which accounts for 90-95% of all cases. IDDM occurs in childhood, and those suffering from the disease require insulin doses throughout their lives. NIDDM generally occurs in adults and, although insulin may be required, the disease may be controllable with oral medication, weight loss, a nutritious diet and a regular exercise program.
Diabetes affects about 16 million people in the U.S. and over 100 million people worldwide. Diabetes can lead to severe health complications associated with the accumulated affects of poor blood glucose control, including blindness, kidney failure, heart failure, and peripheral neuropathy associated with limb pain, poor circulation, gangrene and subsequent amputation (Davidson, Diabetes Mellitusxe2x80x94Diagnosis and Treatment, 3rd Edition, Churchill Livingstone, N.Y., 1991). As a result, frequent self-monitoring of blood glucose is crucial for effective treatment and for reducing diabetes-associated morbidity and mortality.
Currently glucose measurements are done by pricking a finger and extracting a drop of blood, which is applied to a test strip, causing a color reaction between blood glucose and chemicals on the test strip that can be analyzed by an optical meter (glucometer) to give a numerical glucose reading. However, the current glucose tests are painful, disrupt daily life, and may be difficult to perform in long term diabetic patients due to calluses on the fingers and poor circulation. As a result, the average diabetic patient tests his/her blood glucose levels less than twice a day, far fewer than the recommended 4-7 times a day, leading to poor blood glucose control.
A non-invasive glucose monitoring method that is fast, painless and convenient could provide adequate control and greatly reduce the complications commonly seen in diabetes patients and consequently reduce health care costs.
Several types of non-invasive glucose monitoring techniques have been proposed. These techniques measure glucose levels in blood, interstitial fluid, ocular fluids and sweat and include microdialysis, wick extraction, implanted electrochemical or competitive fluorescence sensors, extraction fluid techniques (iontophoresis, skin suction and suction effusion techniques) and optical techniques, such as near-infrared spectroscopy, infrared spectroscopy, Raman spectroscopy, photoacoustic spectroscopy, scatter and polarization changes.
Currently, the most actively studied non-invasive methods for blood glucose measurement are optical techniques. All are limited by low signal-to-noise ratios and poor reproducibility. Current instrumentation lacks specificity due to substantial chemical and physical interference.
Several patents have discussed the use of magnetic fields for the non-invasive detection of certain substances in the human body systems. In nuclear magnetic resonance (NMR), for example, permanent magnets have been used to create a first, or biasing magnetic field to align initially randomly oriented hydrogen protons present in the nuclei of a substance in the sample being tested. A second energy field is applied to increase the energy level of the nuclei. When the second energy field is allowed to collapse, the nuclei return to their original, unaligned state, releasing energy that is detected and analyzed in the form of an image or spectrum. Such spectra are characteristic of individual substances. As a result, NMR may be used to establish the presence and identity of such substances and the concentrations in which such substances are present.
French Patent No. 2,562,785 (Jeandey et al.) discusses a permanent magnet system for NMR imaging medical diagnostics using pole pieces separated by and bridging stacked permanent magnets to form an open examination area and electromagnetic coils to adjust the resulting magnetic field.
Japanese Patent No. 56-14145 (Nippon Denshi K. K.) discusses an arrangement of permanent magnets held within a cylinder. A spacer is placed within the cylinder and sandwiched about the spacer are a pair of cylindrical pole pieces having raised central portions that extend into the air gap between the pole pieces and from which the operative flux emanates.
U.S. Pat. Nos. 4,875,486 and 5,072,732 (Rappaport et al.) describe nuclear magnetic resonance apparatus for non-invasive blood glucose testing that includes a pair of opposed biasing permanent magnets, a surface coil apparatus mounted adjacent the biasing magnets, and an electronic circuit controlled by a microprocessor. The microprocessor activates an RF generator and a cyclically-operated gate, which excites the surface coil. The surface coil applies a second magnetic field, raising the energy state of glucose molecules in a patients finger and aligning their nuclei. The microprocessor then deactivates the RF generator, permitting the nuclei (dipoles) to relax and return to their original alignment, releasing energy that is detected by the surface coil and analyzed by the microprocessor. The process is repeated with a standard sample and the test results with the patient""s finger are compared with the results obtained with the standard sample to determine the glucose concentration in the patient.
I have discovered a novel amplifier for substantially noise-free transmission of an Rf signal. Such an amplifier has many applications, including its use in apparatus for detection or quantitation of an analyte in a sample, such as a non-invasive glucose test apparatus for diabetic patients.
According to one embodiment of the invention, an amplifier is provided that comprises: (a) a plurality of spaced-apart permanent magnets that generate a magnetic field; (b) at least one transmission node, and at least one reflection node spaced apart from the transmission node with a gap therebetween, that are disposed within the magnetic field, the transmission and reflection nodes comprised of an electrically-conductive material; and (c) a source that generates an Rf signal having a selected frequency spectrum that is connected to the transmission node and reflection node, such that a detectable Rf signal is received by the reflection node. The magnets are preferably high-gauss magnets of grade 26 to grade 60, including but not limited to NdFeB magnets. As described below, permanent magnets of grade 36 to 41 have been used in apparatus for detection of glucose in a biological sample. For use in such apparatus, the transmission node and reflection node are preferably each in close proximity to one of the magnets to improve the Rf signal received by the reflection node. A magnetically permeable and electrically insulating barrier is optionally disposed between each node and said magnet in close proximity thereto to prevent contact between the nodes and magnets. An Rf source producing an Rf signal having a frequency of about 2 GHz to about 3 GHz has been successfully used in apparatus for detection of glucose, although other frequencies, or a broad spectrum of frequencies, may be used for other purposes. In order to analyze the Rf signal received by the reflection node, such an apparatus may further include an analyzer connected to the transmission node and the reflection node.
One embodiment of an apparatus that employs such an amplifier is an apparatus for detection or quantitation of an analyte in a sample, such as, for example, a biological sample such as a bodily fluid, tissue, or body part (e.g., a finger). For such purposes, the apparatus described above includes a space or receptacle between the transmission node and reflection node for receiving such a sample and an analyzer. An Rf signal having a magnitude at a characteristic frequency is detectable by the analyzer when the sample is placed in the space or receptacle, the magnitude at the characteristic frequency is reduced as a function of analyte concentration. Such an apparatus may be used, for example, for detection of a biological molecule, such as glucose, proteinaceous molecules and macromolecules (e.g., hemoglobins, virus particles, etc.), in a sample.
According to another embodiment of the invention, methods are provided for causing an Rf signal to be transmitted between spaced-apart transmission and reflection nodes. Such methods comprise: (a) providing at least one transmission node, and at least one reflection node spaced apart from the transmission node with a gap therebetween, the transmission and reflection nodes comprised of an electrically-conductive material, and, connected to the transmission node and a reflection node, a source that generates an Rf signal having a selected frequency spectrum; and (b) disposing the transmission node and the reflecting node in a magnetic field produced by a plurality of spaced-apart high gauss permanent magnets.
According to another embodiment of the invention, methods are provided for detecting an analyte in a sample comprising: (a) providing an apparatus comprising (i) a plurality of spaced-apart permanent magnets that generate a magnetic field; (ii) at least one transmission node, and at least one reflection node spaced apart from the transmission node with a gap therebetween, that are disposed within the magnetic field, the transmission and reflection nodes comprised of an electrically-conductive material; (iii) a source that generates an Rf signal having a selected frequency spectrum that is connected to the transmission node and reflection node; and (iv) an analyzer connected to the transmission node and reflection node; (b) disposing a sample comprising an analyte between the transmission node and reflection node; and (c) using the analyzer to detect a reduction in the amplitude of the Rf signal at a frequency that is characteristic of the presence of the analyte. In order to quantitate the concentration of the analyte in the sample, the method may further comprise (d) determining the reduction of the amplitude of the Rf signal at the frequency that is characteristic of the presence of the analyte, and (e) determining the concentration of the analyte on the basis of said reduction of the amplitude.
The foregoing and other features and advantages of the invention will become more apparent from the following detailed description and accompanying drawings.